Derivatives of 9-deazaguanines are known and include compounds having the following formula: ##STR1## wherein X can be a substituted or unsubstituted aryl ring, 5 or 6 member heterocyclic ring, alicyclic ring, or an alkyl group;
Y can be H, alkyl, CH.sub.2 CN, CH.sub.2 CONH.sub.2, CH.sub.2 CO.sub.2 H, or CH.sub.2 CO.sub.2 alkyl and Q can be H, alkyl, CF.sub.3 or phenyl. For instance, see U.S. Pat. Nos. 4,923,872, 4,985,433, 4,985,434, 5,008,265, 5,008,270, and 5,189,039 and WO 90/10631, disclosures of which are incorporated herein by reference. Also, see Montgomery et at., J. Med. Chem. 1993, 36, 55-69. PA1 Q is a member selected from the group consisting of hydrogen, C.sub.1 -C.sub.3 alkyl, CF.sub.3 and phenyl; and PA1 Y is selected from the group consisting of: hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkyl CN, C.sub.1 -C.sub.4 alkyl CONH.sub.2, C.sub.1 -C.sub.4 alkyl CO.sub.2 H, and C.sub.1 -C.sub.4 alkyl CO.sub.2 C.sub.1 -C.sub.4 alkyl.
Derivatives of 9-deazaguanine are useful as inhibitors of the enzyme purine nucleoside phosphorylase (PNP, EC 2.4.2.1) as discussed by Montgomery, Med. Res. Rev. 1933, 13, 209-228, and some have exhibited efficacy in clinical trials. For instance, see Montgomery et al., Drugs Future 1993, 18, 887-890. Various 9-deazaguanine derivatives also exhibit selective inhibition of T-cells and suppress cellular immunity. They can be used for treating autoimmune diseases, transplant rejection, psoriasis or gout in mammals. Moreover, certain of them potentiate the antiviral and antitumor effect of antiviral or antitumor purine nucleosides.
The synthesis of compounds of the above formula I has been previously approached by two pathways (Schemes I and IB. The approach depicted in Scheme I (where Y=H) was described in U.S. Pat. No. 4,923,872 (see FIG. 1). However, it is not suitable for preparing the wide range of compounds depicted by the above formula I.
Scheme II (see FIG. 2) depicts the synthetic approach described by Montgomery et al., J. Med. Chem. 1993, 36, 55-59, which was based on Lim et al., J. Org. Chem., 1979, 44, 3826-3829; Lim et al., Tetrahedron Lett. 1981, 22, 25-28; and Lim et al., J. Org. Chem. 1983, 48, 780-788.
The procedure depicted in Scheme II suffers many drawbacks: the number of steps (10) involved led to poor overall yields; starting materials and reagents were very expensive, resulting in a procedure that was not economically feasible; several reagents were difficult to use and dangerous (pyrophoric, lachrymatory) on large scale; moisture had to be excluded on several steps, which is sometimes difficult on large scale; there were several isolations and manipulations (chromatography, pressure reaction) which were difficult on large scale; there was a relatively large usage of halogenated solvents on several steps, which poses a costly and environmentally unsound waste disposal problem.
Large quantities of the compounds of the above formula I have been desired for clinical studies. However, the procedures listed in both Schemes I and II are not appropriate for large-scale synthesis. Therefore, a new synthetic procedure was required to economically provide sufficient quantities of compounds of the above formula I.